Post-Traumatic Stress Disorder (PTSD) is a unique psychiatric condition characterized by a persistent maladaptive reaction resulting from exposure to a stressful traumatic event(s). In the United States general population PTSD has a lifetime prevalence of 5 percent in men and 10 percent in women. PTSD is known to produce alternations in the central and autonomic nervous system and hormonal dysregulation. However, little is known about the long-term consequences of PTSD on the cardiovascular system. PTSD is a common disorder among reservation-dwelling American Indians (AIs) with a life-time prevalence of 12 percent in men and 23 percent in women. Similarly, cardiovascular disease (CVD), has emerged as a major health problem in AIs during the past decade. We propose to examine the relationship between PTSD and cardiac function in a population-based sample of AIs. The technical aims of this study involve: 1) the identification of AI men and women ages 18-52 who have a lifetime history of PTSD and are free from overt CVD; 2) the selection of an age-, sex-, and tribe-matched comparison group of AIs who have no history of PTSD and are free from known CVD; 3) a comprehensive lifestyle and clinical evaluation of the PTSD and non-PTSD groups to assess CVD risk factors such as smoking, exercise, obesity, blood pressure, concentrations of blood lipids, and inflammatory and thrombogenic factors; and 4) a set of non-invasive tests of subclinical CVD and other measures of CVD risk. These tests include positron emission tomography (PET) myocardial perfusion imaging to examine coronary flow reserve, high-resolution ultrasound of the carotid arteries to measure carotid intima-media thickness, high-resolution ultrasound of the brachial artery to determine flow-mediated vasodilation, and ambulatory electrocardiographic monitoring, to assess heart rate vadability (HRV). With these data, we will address our scientific aims, which are: 1) to determine whether individuals with PTSD, compared with those without PTSD, show greater evidence of subclinical CVD, including a lower coronary flow reserve, increased carotid intima-media thickness, and reduced forearm flow-mediated vasodilation; 2) to ascertain whether HRV is lower in individuals with PTSD compared to those without PTSD; and 3) to investigate the role of lifestyle (e.g., smoking, alcohol use, exercise, obesity), cultural (e.g., acculturation, religiosity), and biological (e.g., blood pressure, blood lipid and glucose concentrations) mediators in the relationship of PTSD with coronary flow reserve and HRV. Since the emerging epidemic of CVD in AIs cannot be completely explained by changes in traditional risk factors, there is an urgent need to identify novel risk factors, like PTSD. Furthermore, the description of the influence of PTSD on the cardiovascular system could have immediate clinical and public health implications. Strategies for preventing PTSD, initiation of early treatment, and the identification of factors that mediate its potentially cardio-toxic effects could reduce morbidity and mortality from CVD.